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This review summarizes mechanisms including reactive oxygen species (ROS) overproduction, mitochondrial DNA (mtDNA) damage, impairment of oxidative phosphorylation, and mitochondrial permeability transition pore (mPTP) activation. These mitochondrial alterations lead to adenosine triphosphate (ATP) depletion, apoptosis, and renal injury. In addition to apoptotic pathways, necrotic cell death can also be triggered, further aggravating kidney damage. Furthermore, GEN has been reported to directly interfere with mitochondrial ribosomes and gene expression, highlighting mitochondria as both targets and amplifiers of cellular toxicity. Therapeutic approaches targeting mitochondrial integrity, including antioxidants and mitochondrial transplantation, demonstrate potential nephroprotection. Additional strategies such as mPTP, stimulation of mitochondrial biogenesis, and pharmacological modulators of mitochondrial respiration have also shown promise in experimental studies. Understanding mitochondrial mechanisms underlying gentamicin-induced renal injury is crucial for developing targeted therapeutic strategies. A more comprehensive knowledge of mitochondrial regulation, organelle crosstalk, and early biomarkers of dysfunction will facilitate translation into clinical practice. Overall, preserving mitochondrial function represents a promising avenue for reducing nephrotoxicity while maintaining the antibacterial efficacy of GEN.<\/jats:p>","DOI":"10.1007\/s00204-026-04310-5","type":"journal-article","created":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T19:53:50Z","timestamp":1770494030000},"page":"1685-1697","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeting the powerhouse: the mitochondrial perspective on gentamicin-induced kidney injury"],"prefix":"10.1007","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0149-3065","authenticated-orcid":false,"given":"Busra","family":"Korkut Celikates","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7331-1975","authenticated-orcid":false,"given":"Sinem","family":"Ilgin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melis Umay","family":"Yilmaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6131-3399","authenticated-orcid":false,"given":"Ozlem","family":"Atli Eklioglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,7]]},"reference":[{"issue":"4","key":"4310_CR1","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1111\/jphp.12534","volume":"68","author":"SA Abuelezz","year":"2016","unstructured":"Abuelezz SA, Hendawy N, Abdel Gawad S (2016) Alleviation of renal mitochondrial dysfunction and apoptosis underlies the protective effect of sitagliptin in gentamicin-induced nephrotoxicity. 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